Approximately 35 million people are infected with HIV worldwide. HIV enters the central nervous system (CNS) soon after initial infection, infecting primarily macrophages. Infected cells produce new virus and act as viral reservoirs within the CNS, enabling HIV to escape the effects of combinatorial anti-retroviral therapy (cART). Infected macrophages also release neurotoxic factors that contribute to the development of neuroinflammation and HIV-associated neurocognitive disorders (HAND). HIV+ drug abusers are especially vulnerable to the accelerated development of HIV-associated neuropathogenesis, and more than 10% of HIV+ individuals around the world abuse drugs. The mechanisms by which illicit drugs contribute to HIV-associated CNS damage are unclear, but all addictive substances increase extracellular dopamine in the CNS. We showed dopamine increases HIV replication in human macrophages by increasing the entry of the virus into these cells. The dopamine concentration that increases HIV entry is present in the CNS as a result of most types of drug abuse, indicating that CNS macrophages in HIV infected drug abusers are exposed to elevated dopamine. Thus, drug abuse could increase HIV entry into macrophages as soon as the virus enters the brain, rapidly expanding the size of the CNS reservoir and accelerating the development of HAND. The CNS is seeded before the initiation of cART, and even during cART low-level viral replication can persist in the CNS. Additionally, HIV+ drug abusers have poor adherence to cART and drug use during a break from therapy could significantly enhance the impact of the viral rebound. Thus, understanding the impact of dopamine on HIV infection of macrophages is essential to treatment of HIV+ drug abusers, even in the era of cART. This proposal will address this issue using both in vitro systems and a primate model of acute CNS infection in the presence of elevated dopamine. Our in vitro studies will precisely characterize the mechanism(s) by which dopamine increases HIV entry, suggesting new targets to be exploited as the basis for novel entry inhibitors or therapeutic strategies. The primate model will demonstrate the impact of dopamine in acute CNS infection in vivo, and provide a scaffold in which to examine the use of dopamine receptor antagonists with pre-exposure prophylaxis (PrEP) regimens, or as adjuvant therapy to be administered with cART in HIV+ drug abusers or others using therapeutics which affect the dopaminergic system. This system will also characterize the impact of dopamine on CNS infection and the neuroimmune response, providing contraindication data for clinicians using dopaminergic drugs in HIV+ individuals.